Impaired FXR-Syntaxin 1A Pathway Contributes to Diabetic β-Cell Secretory Dysfunction.

Authors

Simian Lv, Bingfeng Li, Xiaosong Ma, Renjie Lv, Chao Lv, Zhuo Mao, Xiangchen Kong, Ying Ying, Pengxia Zhang

Published in

Molecular and cellular endocrinology. Pages 112927. Sep 23, 2026. Epub Sep 23, 2026.

Abstract

Impaired insulin secretion, a hallmark of type 2 diabetes (T2D), is associated with the downregulation of syntaxin 1A (encoded by Stx1a), a core SNARE protein essential for insulin exocytosis, in pancreatic β-cells. However, the mechanism regulating syntaxin 1A expression remains unclear. This study aimed to determine the role of the nuclear receptor farnesoid X receptor (FXR) in modulating syntaxin 1A expression. We demonstrated that syntaxin 1A expression was significantly reduced in islets from diabetic Goto-Kakizaki (GK) rats and in INS-1 832/13 cells exposed to chronic high glucose. FXR levels were similarly diminished under these diabetic conditions. Genetic knockdown or knockout of FXR in β-cells markedly decreased syntaxin 1A expression and impaired glucose-stimulated insulin secretion (GSIS). Conversely, activation of FXR with GW4064 or chenodeoxycholic acid (CDCA) robustly upregulated syntaxin 1A expression. Chromatin immunoprecipitation assays revealed that FXR activation enhanced its binding to a conserved response element in the Stx1a promoter, facilitating the recruitment of the coactivator steroid receptor coactivator-1 (SRC-1) and increasing histone H3 acetylation, an epigenetic marker for active transcription. Intriguingly, FXR also promoted its own expression through a positive autoregulatory loop. Collectively, these findings identify FXR as a key transcriptional regulator of syntaxin 1A in β-cells. The impairment of the FXR-syntaxin 1A pathway contributes to the secretory dysfunction of diabetic β-cells, revealing a novel pathogenic mechanism underlying T2D.

PMID:
42778018
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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